The compounds of formula I are useful intermediates for preparing pharmaceutically active substances, which have central nervous system anti-depressant effects by inhibiting re-uptake of the neurotransmitters, norepinephrine and serotonin. An example of such antidepressants is Venlafaxine (see Merck Index Twelfth Edition 1996, No. 10079). As disclosed in U.S. Pat. No. 4,535,186, the compounds of formula I can be produced by coupling a cycloalkanone or a cycloalkenone with an appropriately substituted phenylacetonitrils (step 1), and then catalytic hydrogenation of the coupled phenylacetonitriles (step 2). The present invention is related to an improvement of the second step reaction.
According to the preparation method disclosed in the '186 patent, the coupled phenylacetonitrile is hydrogenated over rhodium on alumina catalyst. However, the use of an Rh/Alumina catalyst is not desirable in terms of manufacturing costs, and thus, Rh/Alumina catalyst is not considered practical for industrial scale synthesis.
PCT WO 02/50017 discloses a process for preparation of phenethylamine derivatives by hydrogenation of phenylacetonitriles in the presence of a nickel or cobalt catalyst. Exemplification of PCT WO 02/50017 teaches a hydrogenation process carried out using a pretreated nickel or cobalt catalyst, for example, Raney nickel or Raney cobalt, in an organic solvent, such as alcohol, in the presence of a base, such as NH3, NH4OH, NaOH at a temperature of 27° C. to 60° C.
A process employing a nickel or cobalt catalyst is considered to meet practical, economic considerations. However, some nickel or cobalt catalysts, for example, Raneyl nickel or Raney cobalt, are alkaline in their manufactured forms, and thus, require pretreatment with an acid, which is a cumbersome procedure. Furthermore, hydrogenation of nitrile compounds is usually conducted in a basic condition, such as an ammonia solution, because hydrogenation conducted in an acidic condition generally produces more undesired secondary or tertiary amines rather than desired primary amines as depicted in the scheme below, and the reaction may proceed slowly. In light of this, the pretreatment of a nickel or cobalt catalyst with an acid is not desirable.
It has been found that if hydrogenation of phenylacetonitriles in the presence of a nickel or cobalt catalyst is conducted under a basic condition at above room temperature such as those used in the process disclosed in PCT WO 02/50017, such a hydrogenation reaction results in cracking of the starting nitrile compounds to produce 4-methoxyphenylacetonitrile, which may be hydrogenated to produce 4-methoxyphenethylamine impurities, as shown below.

The present invention is based in part on a finding that hydrogenation of coupled phenylacetonitriles using a nickel or cobalt catalyst in a basic condition at a higher temperature produces substantial amounts of phenalkylamine impurities. The phenalkylamine impurities are very similar to the desired end products of primary amines in terms of physical and chemical properties, and thus, it is very difficult to separate them from the desired end products.
The improvement of reducing impurities, in particular, impurities that are difficult to separate, is an advantage over previously known processes.